Intratympanic Gels for Inner Ear Disorders: A Scoping Review of Clinical Trials.

OBJECTIVE: Intratympanic injections are a safe, well tolerated procedure routinely performed by ENT's specialists. Intratympanic injections of gels have the potential to deliver therapeutics into the cochlea through the round window membrane prolonging the release of drugs in the inner ear compartment. Aim of the present review is to summarize clinical trials testing pharmacological treatments for inner ear pathologies through intratympanic gel formulations. DATA SOURCES: Online databases (Google scholar and PubMed) and registers (Clinicaltrials.gov and Euclinicaltrial) were used to identify clinical trials performed between 1990 and 2022. REVIEW METHODS: PRISMA criteria have been followed. Clinical trials testing gel formulations administered through local intratympanic injections and targeting inner ear disorders were included. All the reports were identified by the authors working in pairs sequentially selecting only studies respecting the inclusion criteria. RESULTS: A total of 45 clinical studies have been noticed; the gels for intratympanic injection are in the form of poloxamers or hyaluronic acid combinations; the trials found target different kind of inner ear disorders: acquired-stable SNHL, tinnitus, acute sudden SNHL, Meniere disease, cisplatin induced ototoxicity and hearing preservation in patients undergoing cochlear implant surgery. CONCLUSION: Few studies listed do not provide the specific kind of gel formulation used but only report the intratympanic delivery vehicle as "gel" or "thermogel". Multiple clinical studies have been targeting several forms of inner ear disorders by injecting different compounds through poloxamer and hyaluronic acid formulations. Larger and more advanced clinical stages are necessary to confirm the efficacy of these chemical compounds.

Steroid Efficacy on Audiologic Recovery in Patients With Sudden Sensorineural Hearing Loss and Vestibular Schwannoma: A Retrospective Review.

OBJECTIVES: The objectives of this study are to (i) estimate the incidence of vestibular schwannoma (VS) among patients in an integrated healthcare system who present for evaluation of sudden sensorineural hearing loss (SSNHL) and (ii) evaluate the efficacy of empiric steroid therapy on audiologic recovery among SSNHL patients ultimately diagnosed with VS. METHODS: A retrospective chart review was performed on patients presenting with SSNHL in 2021 at a multicenter integrated healthcare system serving over 4 million members. Patient demographics, audiometric data, VS diagnosis, therapeutic steroid intervention, and data regarding treatment response were recorded. A clinically significant audiometric improvement was defined as (i) an increase of 15% in word recognition score, (ii) a decrease of 15 dB in four-frequency pure-tone average (PTA) using frequencies of 500, 1000, 2000, and 4000 Hz, or (iii) a PTA of <20 dB on follow-up audiogram. RESULTS: Six hundred fifty-eight patients were reviewed, of which 309 (56.0% male; mean, 57.5 years) met the inclusion criteria with audiometric data and magnetic resonance imaging data. Ten patients (70.0% male; mean, 51.3 years) were found to have VS. Of these, five patients received oral steroid therapy alone, and five had combination therapy (oral + intratympanic steroid injections). No patients received intratympanic steroid therapy alone. Median PTA improvement with steroid therapy was 3.1-dB hearing loss, and median word recognition score improvement was 16.5%. Six of 10 patients demonstrated clinically significant audiometric improvement with steroid therapy. CONCLUSION: This study represents the largest US-based study showcasing the prevalence of VS in patients originally presenting with SSNHL. It also reinforces previous findings that VS does not preclude trials of steroid therapy.

A randomized, double-blind, placebo-controlled phase 2 study of intratympanic OTO-313 in patients with moderate to severe subjective tinnitus.

PURPOSE: This was a randomized, double-blind, placebo-controlled Phase 2 study to evaluate the efficacy and safety of intratympanic OTO-313 in patients with subjective unilateral tinnitus. METHODS: Patients with moderate to severe unilateral tinnitus of 2-12 months duration were enrolled. A single intratympanic injection of OTO-313 or placebo was administered to the affected ear and patients were evaluated during a 16-weeks follow-up period. Efficacy was assessed using the Tinnitus Functional Index (TFI), daily ratings of tinnitus loudness and annoyance, and Patient Global Impression of Change (PGIC). RESULTS: Intratympanic administration of OTO-313 and placebo produced reductions in tinnitus with a similar percentage of TFI responders at Weeks 4, 8, 12, and 16. Reductions in daily ratings of tinnitus loudness and annoyance, and PGIC scores were also similar between OTO-313 and placebo groups. No significant differences in mean TFI scores between OTO-313 and placebo were observed for pre-specified strata regarding tinnitus duration (≥ 2 to ≤ 6 months and > 6 to ≤ 12 months) and TFI baseline scores (≥ 32 to ≤ 53 points and ≥ 54 to 100 points), although the results numerically favored OTO-313 in patients in the ≥ 2 to ≤ 6 months strata. These results also demonstrated an unexpectedly high placebo response particularly amongst patients with chronic tinnitus, despite training implemented to mitigate placebo response. OTO-313 was well-tolerated with a similar incidence of adverse events compared to placebo. CONCLUSIONS: OTO-313 did not demonstrate a significant treatment benefit relative to placebo due in part to a high placebo response. OTO-313 was safe and well-tolerated.

Hearing loss and COVID-19: an umbrella review.

INTRODUCTION: COVID-19 can result in an extensive range of extrapulmonary, and neurological signs and symptoms such as olfactory and/or taste dysfunction, and otologic symptoms. The aim of this study was to investigate the hearing loss manifestation from COVID-19. METHODS: The goal of this umbrella review was to examine hearing loss associated with COVID-19 disease. English literature published until October 15, 2022 in online databases including PubMed, Scopus, Web of Science, and Embase was considered for this purpose. Eligibility of the articles for subsequent data extraction was evaluated in a two-step selection process with consideration to an inclusion/exclusion criterion. This review followed the PRISMA protocol and the Amstar-2 checklist for quality assessment. RESULTS: A total of four treatment strategies were used by different studies which included oral corticosteroids, intratympanic corticosteroids, combined oral and intratympanic corticosteroids, and hyperbaric oxygen therapy. Five studies investigated corticosteroid use in the forms of oral or intratympanic injection; four studies reported (complete or partial) hearing improvements after steroid treatment, while one study stated no significant improvement in hearing function. One study reported that oral corticosteroid monotherapy alone was not effective, while vestibular symptoms were ameliorated by a combination of oral prednisone, intratympanic dexamethasone injection, and hydroxychloroquine. CONCLUSION: The findings suggest that despite being one of the rare complications of COVID-19, hearing loss can impact a patient's quality of life. The most common type reported was sensorineural hearing loss, which can be diagnosed with variable techniques.

The impact of eustachian tube function on intra-tympanic steroid administration.

OBJECTIVES: This study investigated the impact of eustachian tube (ET) function (ETF) on therapeutic success on candidates for intra-tympanic administration of steroids (ITAoS), due to idiopathic sudden sensorineural hearing loss (ISSNHL). METHODS: Medical chart review in two university-affiliated medical centers was performed. Included were consecutive adult patients diagnosed with unilateral ISSNHL between 2012 and 2019 who were treated with ITAoS due to incomplete or no recovery following systemic steroidal therapy. ETF was assessed by means tympanometry, before the initiation of ITAoS. The cohort was divided into an ET dysfunction group (ETD(+)) and a functioning ET group (control: ETD(-)). The audiologic response to treatment was recorded at the last follow-up. RESULTS: A total of 64 suitable patients [median (interquartile, IQR) age 49 (38-63) years] were enrolled. The ETD(+) group included 20 patients and the remaining 44 patients served as controls. Demographic and clinical parameters were not significantly different between the two groups at presentation. Hearing thresholds were improved significantly better, at frequencies 250, 500, 1, 2, 4, and 8 kHz (p = 0.001-0.040) in the ETD(+) group. CONCLUSION: ETD(+) is associated with better efficacy of ITAoS.

Long-term exposure to high-concentration dexamethasone in the inner ear via intratympanic administration.

The first-line treatment for inner ear disorders is usually oral/systemic steroids. Intratympanic steroid therapy is an alternative option; however, it requires multiple office visits owing to the short residence time of steroids in the inner ear (systemic: 24 h, intratympanic: 2-3 h). Therefore, intratympanic injections of higher steroid concentrations could result in longer drug exposure, providing better treatment outcomes. This study aimed to develop a prototype for high-concentration steroids and examine their safety and feasibility in vivo. Using wild-type Institute for Cancer Research mice, high-concentration steroids (50 mg/mL dexamethasone), typical steroid concentrations (3.3 mg/mL dexamethasone), and sterile saline were administrated into the middle ear cavity via tympanic membrane injection. Auditory brainstem response analysis, vestibular function tests, and morphological analyses were performed to examine the safety and utility of High-conc Dex. One month post-injection, the frequency-averaged auditory brainstem response thresholds of high-dose dexamethasone-treated mice were not significantly different from those of low-dose dexamethasone- and saline-treated mice at all tested frequencies. Furthermore, the total points on vestibular function tests were similar between the three groups. Morphologically, no damage to the inner ear/middle ear mucosa was observed in all groups. Two months post-injection, dexamethasone could still be detected in the high-dose dexamethasone group. Altogether, our data successfully demonstrates the feasibility and safety of high-dose dexamethasone for in vivo use in the middle ear and ensure that the drug localizes to the inner ear. Further research is warranted to develop this new treatment strategy and further characterize its effects in vivo.

Evaluation of prednisolone and prednisolone sodium succinate concentrations in human plasma and inner ear perilymph during cochlear implantation 24 h after intratympanic injection.

BACKGROUND: The use of intratympanic (IT) steroids has drastically increased over the past 10-15 years to manage many otological pathologies. OBJECTIVES: This study aimed to compare the concentrations of prednisolone and prednisolone sodium succinate (SS) in the plasma and inner ear perilymph of participants who underwent cochlear implantation 24 h after IT injection. MATERIALS AND METHODS: It was a prospective comparative randomized study. Twenty participants received an IT injection of prednisolone SS ∼24 h before the cochlear implantation. The other five participants received an IT saline injection and represented the control group. Perilymph and blood were sampled during the cochlear implantation surgery. RESULTS: Both prednisolone and prednisolone SS were still present in perilymph ∼24 h after the IT administration. Only prednisolone was present in the blood plasma of seven participants (35%). CONCLUSION: IT injection of prednisolone SS resulted in high perilymph concentrations of prednisolone and prednisolone SS, which could stay in the perilymph for at least 24 h. Using a mini-endoscope during the IT injection may effectively detect barriers infront of the round window membrane, increasing the drug concentration in the inner ear. SIGNIFICANCE: IT injection is an effective method for delivering prednisolone to the inner ear.

Standardization of Outcome Measures for Intratympanic Steroid Treatment for Idiopathic Sudden Sensorineural Hearing Loss.

OBJECTIVE: To identify variability in reported hearing outcomes for intratympanic (IT) steroid treatment of idiopathic sudden sensorineural hearing loss (ISSNHL) by comparing outcomes using the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) guideline with other published criteria. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary otology practice. PATIENTS: Patients with ISSNHL treated with IT steroid between April 2003 and December 2020. INTERVENTIONS: IT steroid injection and audiometric evaluation. MAIN OUTCOME MEASURES: 1) Rates of full, partial, or no recovery using the AAO-HNS guideline versus other reported criteria, and 2) correlation analyses of demographic and clinical variables with response to IT steroid. RESULTS: Using AAO-HNS reporting criteria, full recovery of the pure-tone average was noted in 25.68% of patients. Applying eight other published outcomes criteria to this patient cohort classified full recovery in 14.87 to 40.54% of patients. Similarly, AAO-HNS criteria classified "no recovery" in 51.35% of our patients, whereas applying the other reported criteria showed an average rate of 62.16% no recovery and as high as 82.43% of patients without recovery. Younger age ( p = 0.003; effect size, 0.924) and IT injection within a week of onset ( p < 0.001; effect size, 1.099) positively correlated with full recovery. There was no impact of prior or concurrent oral steroids, or number of steroid injections on outcome. CONCLUSION: Great variability exists in the literature for assessment of IT steroid outcomes in ISSNHL. Standard reporting of outcomes as per the AAO-HNS SSNHL guideline is recommended to consistently characterize IT steroid efficacy and allow comparison across studies.

Probability of clinically significant hearing recovery following salvage intratympanic steroids for sudden sensorineural hearing loss in the 'real world'.

OBJECTIVE: This study aimed to determine the probability of hearing recovery in patients with idiopathic sudden sensorineural hearing loss following salvage intratympanic steroids. METHOD: A retrospective review of all patients receiving salvage intratympanic steroid injections for idiopathic sudden sensorineural hearing loss was performed (January 2014 to December 2019). Twenty-two patients were identified, of whom 15 met inclusion criteria. Pre- and post-treatment audiograms were compared with the unaffected ear. Hearing recovery was categorised based on American Academy of Otolaryngology Head and Neck Surgery criteria. RESULTS: Only 1 patient out of 15 (6.7 per cent) made a partial recovery, and the remainder were non-responders. The median duration of time between symptom onset and first salvage intratympanic steroid treatment was 52 days (range, 14-81 days). No adverse reactions were observed. CONCLUSION: 'Real world' patients with idiopathic sudden sensorineural hearing loss present differently to those in the literature. Sudden sensorineural hearing loss should be diagnosed with care and intratympanic steroid injections initiated early if considered appropriate. Patients should make an informed decision on treatment based on prognostic factors and local success rates.

Consensus on intratympanic drug delivery for Menière's disease.

PURPOSE: Intratympanic (IT) drug delivery receives attention due to its effectivity in treatment for Menière's disease (MD). Due to the release of the consensuses and new evidence on IT drug delivery for MD have been published, the review with a view to supplementing the details of IT treatment of MD is indispensable. METHODS: The literatures on IT injection for MD treatment over the last two decades are retrieved, International consensus (ICON) on treatment of Menière's disease (2018), Clinical Practice Guideline (2020) and European Position statement on Diagnosis and Treatment of Meniere's Disease (2018) are taken into account for reference, and follow advice from experts from Europe, USA and China. RESULTS: Experts agree on the following: (1) The effectiveness of IT methylprednisolone (ITM) on vertigo control seems to be somewhat better than that of IT dexamethasone (ITD), and ITM can restore hearing in some cases. (2) Due to the ototoxicity of aminoglycosides, the application of intratympanic gentamicin (ITG) in MD patients with good hearing is conservative. However, some studies suggest that ITG with low doses has no significant effect on hearing, which needs to be further proved by clinical studies with high levels of evidence. (3) Currently, generally accepted treatment endpoint of ITG is no vertigo attack in a 12-month period or a vestibular loss in objective tests in the affected ear. CONCLUSION: More studies with high level of evidence are needed to evaluate the drug type, efficacy, and therapeutic endpoint of IT therapy for MD.

Optimal N-acetylcysteine concentration for intratympanic injection to prevent cisplatin-induced ototoxicity in guinea pigs.

BACKGROUND: Cisplatin is a chemotherapy drug that can induce sensorineural hearing loss. At present, no otoprotective agent is approved for use. OBJECTIVES: This study investigated the optimal concentration of intratympanic N-acetylcysteine (NAC) to prevent cisplatin-induced ototoxicity in a guinea pig model. MATERIALS AND METHODS: Guinea pigs (n = 64) were treated with a single intratympanic injection containing different NAC concentrations or saline (control) 3 days prior to intraperitoneal injection with cisplatin. The threshold change in the auditory brainstem response was assessed. RESULTS: Four weeks after intraperitoneal cisplatin injection, only the group that received 2% NAC exhibited significant otoprotection (p < .05) compared with the control. Otoprotection was observed at all the frequencies tested (1k, 2k, 4k, and 8k Hz). The 2% NAC group also exhibited significant otoprotection (p < .05) compared with the other NAC groups (at 1k, 2k, 4k, and 8k Hz). The 4% NAC group exhibited significantly reduced hearing capacity (p < .05) in the fourth week compared with controls. CONCLUSIONS AND SIGNIFICANCE: Intratympanic NAC administration is an efficient and safe means of preventing cisplatin-induced ototoxicity. In our animal model, the optimal intratympanic NAC concentration was 2%; concentrations of 4% loss of otoprotection.

Frequency-specific prediction model of hearing outcomes in patients with idiopathic sudden sensorineural hearing loss.

PURPOSE: The hearing outcome of idiopathic sudden sensorineural hearing loss (ISSNHL) is hard to predict. We herein constructed a multiple regression model for hearing outcomes in each frequency separately in an attempt to achieve practical prediction in ISSNHL. METHODS: We enrolled 235 consecutive in-patients with ISSNHL who were treated in our department from 2015 to 2020 (average hearing level at 250-4000 Hz ≥ 40 dB; time from onset to treatment ≤ 14 days; 126 males/109 females; age range 17-87 years (average 61.0 years)). All patients received systemic prednisolone administration combined with intratympanic dexamethasone injection. The pure-tone hearing threshold of 125-8000 Hz was measured at every octave before (HLpre) and after (HLpost) treatment. A multiple regression model was constructed for HLpost (dependent variable) using five explanatory variables (age, days from onset to treatment, presence of vertigo, HLpre, and hearing level of the contralateral ear). RESULTS: The multiple correlation coefficient increased as the frequency increased. Strong correlations were seen in high frequencies, with multiple correlation coefficients of 0.784/0.830 for 4000/8000 Hz. The width of the 70% prediction interval was narrower for 4000/8000 Hz (± 18.2/16.3 dB) than for low to mid-frequencies. Among the five explanatory variables, HLpre showed the largest partial correlation coefficient for any frequency. The partial correlation coefficient for HLpre increased as the frequency increased, which may partially explain the high multiple correlation coefficients for high frequencies. CONCLUSION: The present model would be of practical use for predicting hearing outcomes in high frequencies in patients with ISSNHL.

Triamcinolone acetonide can be detected in cerebrospinal fluid after intratympanic injection.

Intratympanically applied treatments are of increasing interest to the otologic community to treat sudden sensorineural hearing loss or vestibular disorders but also to deliver gene therapy agents, or biologics to the inner ear. Further diversion from the middle ear and perilymph to blood circulation and cerebrospinal fluid via the cochlear aqueduct are one of the limiting factors and so far not understood well enough. In this study, intratympanically applied triamcinolone acetonide was determined in cerebrospinal fluid. Additionally, perilymph was sampled through the round window membrane as well as at the lateral semicircular canal to determine drug levels. Of the twenty-one included patients, triamcinolone acetonide was quantifiable in cerebrospinal fluid in 43% at very low levels (range 0 ng/ml-6.2 ng/ml) which did not correlate with perilymph levels. Drug levels at the two different perilymph sampling sites were within a range of 13.5 ng/ml to 1180.0 ng/ml. Results suggest an equal distribution of triamcinolone acetonide to semicircular canals, which might support the use of triamcinolone acetonide as a treatment option for vestibular pathologies such as Menièrés disease. On the other hand, the distribution to cerebrospinal fluid might be limiting current approaches in gene therapy where a central distribution is unwanted.

Comparison of two different intratympanic corticosteroid injection protocols as salvage treatments for idiopathic sudden sensorineural hearing loss.

PURPOSE: We aimed to investigate the effect of interval length and total count of intratympanic steroid (ITS) injections in salvage treatment of patients with idiopathic sudden sensorineural hearing loss (ISSNHL). METHODS: This retrospective case-control study included 64 patients with ISSNHL, who were treated with ITS injections as salvage therapy at a tertiary referral centre. From September 2019 to December 2020, 32 patients received up to four injections every 2-4 days (revised-protocol group). These patients were 1:1 matched to patients, who received up to three injections at 1-week intervals between January 2014 and August 2019 (initial-protocol group). Hearing outcomes of the two groups were compared. RESULTS: Both ITS salvage treatment protocols resulted in a statistically significant hearing improvement (p < 0.05). The initial-protocol declined hearing thresholds by 12 ± 11.7 dB (p < 0.001, d = 1, P = 99%). Mean hearing function was improved by 13.4 ± 19.1 dB in the revised-protocol group [p < 0.001, d = 0.7, P = 98%]. A clinically significant hearing improvement (> 10 dB) was seen in 18 patients (58.1%) in the initial-protocol group and in 14 patients (41.9%) in the revised-protocol group. A comparison of the hearing outcomes between protocol groups revealed no statistically significant differences (p > 0.05). CONCLUSION: These results indicate that a shorter injection interval does not lead to better hearing outcomes in ITS salvage treatment for ISSNHL. Moreover, fewer ITS injections may reduce costs, physical/mental stress of the patients and lower the risk of persistent tympanic perforations.

Intratympanic steroid injection versus hyperbaric oxygen therapy in refractory sudden sensorineural hearing loss: a meta-analysis.

OBJECTIVE: The present meta-analysis aims to compare the efficacy of intratympanic steroid (ITS) injection and hyperbaric oxygen (HBO) therapy as salvage treatments for refractory sudden sensorineural hearing loss (SSNHL). DATA SOURCES: Comprehensive searches were performed in PubMed, EMBASE and the Cochrane Library from the date of the database inception to June 2020. All studies reporting the use of salvage ITS and HBO treatments in refractory SSNHL patients were included. Subsequently, the full texts of the eligible studies were evaluated. METHODS: The quality and bias of the studies were assessed using the Newcastle-Ottawa Scale and Cochrane's risk of bias tools for nonrandomized and randomized studies, respectively. The data were analyzed using Comprehensive Meta-Analysis software (Version 3; Biostat, Englewood, NJ). RESULTS: Three hundred and fourteen subjects in 3 observational studies and 1 randomized controlled trial met our inclusion criteria. The pooled results demonstrated that there were no significant differences in the mean posttreatment hearing gain between the ITS and HBO groups. The changes in word discrimination and hearing gain at 250, 500, 1000, 2000, 4000 and 8000 Hz were also comparable between the two salvage treatment groups. CONCLUSIONS: The pooled results demonstrated that there were no significant differences in hearing improvements between salvage ITS injection and salvage HBO therapy after failed primary systemic steroid treatment in patients with SSNHL. However, spontaneous recovery could bias the treatment outcomes, and these results should be interpreted with caution. Clinicians may choose these salvage treatments according to personal experience and treatment availability. In cases in which specialized HBO facilities are difficult to access, salvage ITS injection can be provided with comparable responses.

Tympanic Membrane Perforation After Intratympanic Steroid Injection: A Systematic Review and Meta-analysis.

OBJECTIVE: We investigated the incidence of tympanic membrane (TM) perforations induced after intratympanic steroid injection (ITSI) in patients with sudden sensorineural hearing loss (SSNHL) through a systematic review and meta-analysis. DATA SOURCES: PubMed, Embase, and MEDLINE. REVIEW METHODS: Primary database searches were performed, and 1901 records were identified. After removal of 1802 articles through abstract screening, the remaining 99 full-text journals were assessed for eligibility to be included in the study. Fifty-eight studies that used either ventilation tubing (VT) or tympanocentesis (TC) for ITSI were selected for analysis. The subjects were divided into VT and TC groups. The rate of TM perforation after ITSI in 2 groups, sites of ITSI, needle gauge, and influence on residual hearing were investigated. RESULTS: The cohorts comprised patients who underwent VT (n = 257, 9.6%) and TC (n = 2415, 90.4%). The proportion of TM perforation after ITSI in each group was 0.073 (95% CI, 0.0469-0.1113) and 0.010 (95% CI, 0.0045-0.0215), respectively, which suggested that the VT group showed a significantly higher TM perforation rate than the TC group (P < .001). In the subgroup analyses, there was no significant difference in the odds ratio for the rate of TM perforation according to the injection site and needle gauge for TC. The proportion of surgical repair showed no significant difference between the 2 groups. CONCLUSION: ITSI via VT may have a significantly higher risk of TM perforation than ITSI via TC, although those are relatively small overall. ITSI should be performed in the direction to minimize possible adverse effects.

Evaluation of Levels of Triamcinolone Acetonide in Human Perilymph and Plasma After Intratympanic Application in Patients Receiving Cochlear Implants: A Randomized Clinical Trial.

Importance: The use of intratympanically applied steroids is of increasing interest. Consequently, research has focused on finding an ideal drug that diffuses through the round window membrane and can be retained in the perilymph. Objective: To compare levels of triamcinolone acetonide (TAC) in perilymph and plasma after intratympanic injection. Design, Setting, and Participants: This randomized clinical trial included 40 patients receiving cochlear implants at a single tertiary care center in Vienna, Austria. Patients were randomized to 1 of 4 treatment groups receiving 1 of 2 intratympanic doses of TAC (10 mg/mL or 40 mg/mL) at 1 of 2 approximate time points (24 hours or 1 hour) before sampling the perilymph. Inclusion was carried out between November 2017 and January 2020, and data were analyzed in December 2020. Interventions: All patients underwent intratympanic injection of TAC. During cochlear implantation, perilymph and plasma were sampled for further analysis. Main Outcomes and Measures: Levels of TAC measured in perilymph and plasma. Results: Among the 37 patients (median [range] age, 57 [26-88] years; 18 [49%] men) included in the analysis, TAC was present at a median (range) level of 796.0 (46.4-7706.7) ng/mL. In the majority of patients (n = 29; 78%), no drug was detectable in the plasma after intratympanic injection. Levels above the limit of detection were less than 2.5 ng/mL. The 1-factorial analysis of variance model showed lower TAC levels in the group that received TAC, 10 mg/mL, 24 hours before surgery (median, 271 ng/mL) compared with the group that received TAC, 10 mg/mL, 1 hour before surgery (median, 2877 ng/mL), as well as in comparison with the groups receiving TAC, 40 mg/mL, 24 hours before surgery (median, 2150 ng/mL) and 1 hour before surgery (median, 939 ng/mL). The 2-factorial analysis of variance model showed lower TAC levels in the group receiving TAC, 10 mg/mL, 24 hours before surgery than the group receiving TAC, 10 mg/mL, 1 hour before surgery, and higher TAC levels in the group receiving TAC, 40 mg/mL, 24 hours before surgery compared with the group receiving TAC, 10 mg/mL, 24 hours before surgery. Patients with thickening of the middle ear had statistically significantly higher plasma levels (median, 1.4 ng/mL vs 0 ng/mL) and lower perilymph levels (median, 213.1 ng/mL vs 904 ng/mL) than individuals with unremarkable middle ear mucosa. Conclusions and Relevance: In this randomized clinical trial, TAC was shown to be a promising drug for intratympanic therapies, with similar levels in perilymph 1 hour and 24 hours after injection (distinctly in the groups receiving the 40 mg/mL dose). There was also minimal dissemination to the plasma, especially in patients with unremarkable middle ear mucosa. Trial Registration: ClinicalTrials.gov Identifier: NCT03248856.